Antihypertensive Agents Quiz

Antihypertensive Agents

• Antihypertensive agents are used to treat high blood pressure (HTN).
• Learning objectives include classifying agents by mechanism of action, illustrating BP-lowering mechanisms, comparing drug classes, highlighting emergency use, and indicating pregnancy treatment.

Sympathetic Depressants

• Alpha2-selective agonists are a type of sympathetic depressant.
• Adrenergic neuron blockers (reserpine & guanethidine) are another type.
• Receptors blockers include Alpha₁-receptors antagonists and Beta-receptors antagonists.

Beta Blockers

• Beta blockers are categorized as non-selective or cardio-selective.
• Non-selective examples include propranolol, nadolol, timolol, and pindolol.
• Cardio-selective examples include atenolol, acebutolol, and metoprolol.
• Some beta blockers have intrinsic sympathomimetic activity (ISA), such as pindolol and oxprenolol.
• Beta blockers are classified into three generations based on their ẞ-adrenergic receptor antagonist properties.

Beta Blockers Classification: Three Generations

• First-generation includes nonselective agents like Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, and Timolol.
• Second-generation includes β₁-selective agents like Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, and Metoprolol.
• Third-generation includes β₁-selective agents with vasodilatory properties, like Carvedilol, Carteolol, Labetalol, and Nebivolol.

Beta Blockers: Selectivity and Partial Agonist Activity

• Carvedilol and labetalol also cause α₁ blockade.
• The partial agonist activity of beta blockers may not correspond to the specific receptor type being blocked.

Cardioselective Beta Blockers

• Metoprolol, atenolol, nebivolol, bisoprolol, acebutolol, betaxolol, esmolol are examples.
• They are collectively referred to as “MANBABE”

Beta Blockers Actions

• Beta blockers suppress cardiac function, reducing cardiac work.
• Additional mechanisms for BP reduction include decreasing renin release and blocking presynaptic beta receptors.
• Some beta blockers have membrane stabilizing activity.

Beta Blockers Acute Effects

• Data in the form of graphs demonstrates the effects of beta blockers on cardiac force, arterial pressure, and heart rate.

Beta Blockers Use in HTN

• Chronic use of beta blockers leads to a fall in peripheral resistance in patients with HTN.
• Often used in combination with diuretics or vasodilators.
• Less effective in the elderly and certain racial groups.
• Often valuable in HTN with other cardiovascular conditions.

Beta Blockers Other Actions

• Beta blockers can cause bronchospasm in asthmatic patients.
• They can block liver processes like glycogenolysis, gluconeogenesis and lipolysis.
• They can reduce intraocular pressure (IOP) by decreasing aqueous humor synthesis.
• Some beta blockers have anxiolytic effects.

Beta Blockers CV Use

• Useful for angina, chronic heart failure, and post-myocardial infarction (MI) treatment.
• Can be employed to prevent ventricular arrhythmias due to slow AV conduction.
• Useful in thyrotoxicosis and pheochromocytoma treatment.

Beta Blockers Non-CV Use

• Timolol eyedrops are used for glaucoma treatment
• Can be beneficial for migraine headaches and alcohol withdrawal symptoms.

Nebivolol

• Highly selective β₁-adrenergic receptor blocker.
• Has a vasodilatory effect due to endothelial NO production.
• Does not negatively impact lipid profile.
• Shows improved insulin sensitivity and oxidative stress for an equivalent BP and HR reduction compared to metoprolol in metabolic syndrome patients.

Labetalol

• It exists as a mixture of isomers, one potent non-selective β blocker and the other a potent α₁ blocker.
• The ratio of β:α antagonism is 3:1.
• Available in intravenous (IV) and oral forms.
• Hypotension induced by labetalol is not associated with tachycardia.
• Due to dual blockade (α and β), labetalol is used for hypertensive emergencies and pheochromocytoma.

Carvedilol

• Action is more potent for β receptors compared to α₁ receptors
• Attenuates oxygen-free radical-induced lipid peroxidation and inhibits VSMC mitogenesis independently of adrenoceptor blockade.
• These effects can potentially contribute to the clinical benefits of the drug in chronic heart failure.

Esmolol

• An ultra-short-acting β₁-selective antagonist (~10 minutes).
• Given by continuous infusion.
• Its effects terminate quickly after infusion stops.
• Considered safer than longer-acting agents for asthmatic patients needing β-adrenoceptor antagonism
• Used in supraventricular arrhythmias and perioperative HTN.

Sotalol

• Non-selective β-receptor blocker with marked antiarrhythmic properties.
• Used only in cases of arrhythmia.

Beta Blockers ADRs

• Possible bradycardia and conduction slowing, potentially precipitating heart failure in susceptible individuals.
• Also possible bronchospasm, cold extremities, fatigue, exercise intolerance, hypoglycemic risk, changes in lipid profiles, and issues with sexual function

Beta Blockers Concerns

• Sudden withdrawal can be problematic.
• Cautious use is recommended in patients with peripheral vascular disease.
• Glucagon is the preferred treatment for emergent cardiac adverse effects caused by beta blockers.

Please Note

• Response to beta blockers varies significantly between individuals, with a substantial portion (30-60%) not experiencing adequate blood pressure control; genetic variance may play a role.

ACE Inhibitors

• Frequent treatment for cardiovascular and renal issues, including hypertension, heart failure, and coronary syndrome.
• Chemical structure, potency, bioavailability, half-life, route of elimination, and tissue-bound ACE affinity vary in ACE inhibitors.

ACE Inhibitors Members

• Lisinopril and captopril are prodrugs and need activation by the body
• Perindopril, enalapril, benazepril, quinapril, ramipril, trandolapril, zofenopril, and fosinopril are prodrugs and orally administered.
• Enalaprilat is the only ACE inhibitor available in IV form.

ACE Inhibitors Actions

• Dilate arterioles and venules, reducing TPR and CO.
• Reduce aldosterone release and blood volume.
• Reduce systolic and diastolic BP in hypertensive and normotensive patients.
• Inhibit cardiac and vascular RAAS, resulting in reduced CV remodeling.
• Useful in heart failure and post-MI conditions.

Role In Associated Diseases

• Reduces proteinuria by reducing renal vascular resistance in chronic kidney disease (CKD).
• Beneficial in diabetes, even without hypertension.
• May reduce the onset of frank diabetes in patients with hypertension.

Why Beneficial In Diabetes

• Ang II is linked to insulin resistance (inhibits insulin receptor dependent signaling)
• Reduces insulin-induced NO production in AT1 receptors and activates NADPH oxidase, which creates more ROS and inflammation.
• Can increase tissue Ang II and inhibit NO.
• In diabetic patients, treatment can increase NO activity, improving renal function, and possibly cardiovascular function.

ACE Inhibitors ADRs

• Potential initial hypotension.
• Persistent cough and wheezing.
• Angioedema (significant and potentially life-threatening airway obstruction).
• Mild hyperkalemia.
• Loss of the sense of taste.

ACE Inhibitors Concern 1

• Combination with immunosuppressants (azathioprine) can cause anemia due to erythropoietin reduction.
• Combination with procainamide or allopurinol may increase infection risk (cases of neutropenia).

Ang II Receptors

• AT2 (Ang 1-7, vasodilation, natriuresis) and AT1 (Ang II, vasoconstriction, salt retention) are two types of Ang II receptors.

Renal Effects

• Efferent arterioles largely express AT1 receptors.
• Afferent arterioles largely express AT2 receptors.

ACE Inhibitors Concern 2

• Renal function effects are reversible and depend on baseline renal function.
• Avoid complete discontinuation; dose adjustments are vital, monitored by serum potassium and renal function.
• Be aware of potential hyperkalemia when used with potassium-sparing diuretics.

ACE Inhibitors CIs

• Bilateral renal artery stenosis, ESRD, or nephrosclerosis.
• Caution with acute volume loss (vomiting/diarrhea, as patients may be more susceptible to kidney impairment).
• Avoid use during pregnancy and lactation.
• Avoid use in patients with known hereditary or idiopathic angioedema.
• NSAIDs can reduce ACE inhibitor effectiveness.

Ang II Receptor Blockers (ARBs)

• First marketed ARBs were Losartan and Valsartan
• Azilsartan, candesartan, irbesartan, olmesartan, telmisartan, and eprosartan are also available.
• Selectively bind to AT1 angiotensin receptors in VSMCs, adrenal cortex, kidney, and heart, thus blocking the effects of Ang II.
• Reduce blood vessel constriction, lower VSMC hypertrophy, and reduce vascular remodeling.
• Blood vessels are vasodilated and there is decreased aldosterone secretion with decreased blood volume.
• Reduce cardiac hypertrophy and cardiac remodeling.

ARBs Indications

• Treatment for hypertension, congestive heart failure, and diabetic nephropathy.
• Valsartan is approved for children 6 years and older.
• Replacement option if an ACE inhibitor causes intolerance (like cough or angioedema).

ARBS vs ACE Inhibitors

• More selective for Ang II actions than ACE inhibitors.
• Do not affect bradykinin.
• More vasodilation and hypotensive effects, but not without risk of hyperkalemia and kidney problems
• Less associated with cough and angioedema.
• Same contraindications as ACE inhibitors.
• In diabetic patients, ACE inhibitors are generally preferred for their nephroprotective effects over ARBs.
• Beneficial for patients with heart failure (HF) and chronic kidney disease (CKD).

RAAS Inhibitors Advantages

• Beneficial for HTN with high plasma renin activity.
• Suitable for monotherapy or combined-therapy treatment approaches.
• Prescribed for individuals with hypertension, diabetes, asthma, angina, or heart failure.
• Well-tolerated with minimal risks of edema and electrolyte imbalances, though rare postural hypotension is possible.

RAAS Inhibitors Monitoring

• Regular monitoring of renal function and electrolytes due to drug effects on the renin-angiotensin-aldosterone system (RAAS).
• Adjust dosage or discontinue if potassium levels rise, GFR drops, or creatinine levels elevate.
• Ensure adequate hydration in patients using diuretics before administering RAAS blocking agents.
• Monitor K+ supplementation for patients using diuretics.